Certain benzene derivatives useful in treating cardiac disorders

ABSTRACT

Benzene derivatives of the formula:   WHEREIN R1 represents alkanoyl amino of not more than nine carbon atoms, R2 represents alkyl of one through six carbon atoms, and R3 represents alkyl of one through six carbon atoms or cycloalkyl of three through six carbon atoms, possess pharmacodynamic properties and are useful in the treatment of various cardiac disorders.

United States Patent [1 1 Wooldridge et al.

451 Dec.3l, 1974 1 CERTAIN BENZENE DERIVATIVES USEFUL IN TREATINGCARDIAC DISORDERS [75] Inventors: Kenneth Robert Harry Wooldridge,

Brentwood; Berkeley Basil, l-lighwood, near Chelmsford, both of England[73] Assignee: May & Baker Limited, Dagenham,

, Essex, England [22] Filed: ,Aug. 3, I972 21 Appl. No.: 277,607

Related U.S. Application Data [62] Division of Ser. No. 785,403, Dec.19, 1968, Pat. No.

[ 30] Foreign Application Priority Data Dec. 22, 1967 Great Britain58516/67 May 14, 1968 Great Britain 56513/68 Aug. 2, 1968 Great Britain37103/68 [52] U.S. Cl. 424/324 [51] Int. Cl A6lk 27/00 [58] Field ofSearch 424/324, 330

[56] References Cited UNITED STATES PATENTS 3,408,387 10/1968 Mowe eta1. 260/482 3,726,919 4/1973 Wooldridge et al. 260/562 A PrimaryE.\'aminer-Albert T. Meyers Assistant Examiner-Leonard SchenkmanAttorney, Agent, or FirmStevens, Davis, Miller & Mosher [57] ABSTRACTBenzene derivatives of the formula:

through six carbon atoms, possess pharmacodynamic properties and areuseful in the treatment of various cardiac disorders.

3 Claims, N0 Drawings CERTAIN BENZENE DERIVATIVES USEFUL IN TREATINGCARDIAC DISORDERS This is a division of application Ser. No. 785,403,filed Dec. 19, 1968, now U.S. Pat. No. 3,726,919.

This invention relates to new benzene derivatives.

According to the present invention there are provided the new benzenederivatives of the general formula:

wherein R represents a straightor branched-chain alkanoylamino groupcontaining not more than nine (preferably not more than six)'carbonatoms, R represents an alkyl group, and R represents an alkyl group, ora cycloalkyl group containing from three or six carbon atoms, and theiracid addition salts.

In this specification it is to be understood that the alkyl groupsrepresented by the symbols R and R contain not more than six carbonatoms and may have straightor branched-chains.

The compounds of general formula I exist in stereoisomeric forms and thepresent invention includes all such forms, and mixtures thereof, andtheir acid addition salts.

The new benzene derivatives of formula I and their non-toxic acidaddition salts possess pharmacodynamic properties of value in thetreatment or prophylaxis of various cardiac disorders manifested byangina pectoris and cardiac arrhythmias and, administered in conjunctionwith a sympathetic a-receptor blocking agent, in the relief, prior tosurgery, of the symptoms of pheochromocytoma which are due, as is known,to the presence of high amounts of noradrenaline in the blood stream.

In laboratory screening methods, the new compounds inhibit sympatheticB-receptors in the rat, guinea-pig, cat and dog at doses which do notinhibit sympathetic a-receptors or have other untoward cardiovascularactions. In addition, the compounds show a specificity of action in thatthey have a substantial blocking action on cardiac B-receptors atdosages substantially lower than those required to have a substantialblocking action on sympathetic fi-receptors in bronchial muscle and thevascular system. This property is of particular value in the treatmentof conditions in which blocking sympathetic B-receptors in the bronchiis contraindicated, e.g. in bronchial asthma and various forms ofbronchospasm.

For example, (I) the new compounds block the cardiac sympatheticB-receptors in the guinea-pig at doses between 0.01 and 0.1 mg/kg.animal body weight administered intravenously, which are lower thanthose required to inhibit sympathetic B-receptors on bronchial muscle asdetermined by their ability to reduce isoprenaline-inducedbronchodilatation at doses between 0.15 and 3.0 mg/kg. animal bodyweight administered intravenously and the absence of potentiation ofanaphylactic bronchospasm in this species at doses below 5 -mg./kg.animal body weight administered intravenously. (II) The compounds alsoshow specificity of action in the cat anaesthetized with a mixture ofchloralose and pentobarbital sodium administered intraperitoneally asshown by their inhibition (at doses between 0.025 and 0.1 mg./kg. animalbody weight adadministered pentobarbital sodium as shown by theirministered intravenously) of the positive chronotropic effects uponcardiac muscle of intravenouslyadministered isoprenaline and by theirinhibition (at doses between 0.05 and 0.2 mg./kg. animal body weightadministered intravenously) of the effects of accelerans nervestimulation, as compared with their inhibition (at doses between 0.15and 3.0 mg./kg. animal body weight administered intravenously) of thefall in diastolic pressure produced by intravenouslyadministeredisoprenaline and their inhibition (at doses between 0.5 and 2.0 mg./kg.animal body weight administered intravenously) of the bronchodilatationproduced by intravenously-administered isoprenaline. (III) A specificityof action on sympathetic B-receptors is also shown by the new compoundsin experiments carried out in the dog anaesthetizedwithintravenouslyeffect in inhibiting (at doses between 0.01 and 0.1 mg./kg.animal body weight administered intravenously) the positive inotropicand chronotropic effects upon cardiac muscle ofintravenously-administered isoprenalineand in inhibiting (at dosesbetween 0.02 and 0.2 mg./kg. animal body weight administeredintravenously) the effects of accelerans nerve stimulation, which dosesare lower than the doses required (0.2 to 2.0 mg./kg. animal body weightadministered intravenously) to inhibit the fall in diastolic pressureproduced by intravenously-administered isoprenaline. (IV) In addition,the new compounds correct experimentallyinduced cardiac arrhythmias. Forexample, in the cat anaesthetized with a mixture of chloralose andpentobarbital sodium administered intraperitoneally and in the doganaesthetized with pentobarbital sodium administered intravenously,reversal of the ventricular tachycardia produced by the intravenousadministration of ouabain and a return to normal sinus rhythm isobtained at doses between 3.0 and 30 mg./kg. animal body weightadministered intravenously. They also increase the refractory period ofisolated rabbit atria to electrical stimulation by the method describedby G. S. Dawes, Br. J. Pharmac, Chemother, l, (1946) in concentrationscomparable to the concentrations of quindine which produce a similarincrease in the refractory period.

The compound propranolol, which is used clinically -in the treatment orprophylaxis of angina pectoris and cardiacarrhythmias and, administeredin conjunction with a sympathetic a-receptor blocking agent, in therelief, prior to surgery, of the symptoms of pheochromocytoma, givessimilar results in these tests but does not show specificity of actionon cardiac as opposed to bronchial sympathetic B-receptors.

The benzene derivatives of formula I wherein R is an alkanoylamino groupcontaining not more than six carbon atoms are also useful as startingmaterials for the preparation of corresponding compounds of theaforesaid formula but in which the ketone group COR is replaced by agrouping wherein R represents, for example, a hydroxy, ureido,alkylureido, 'hydroxyalkylureido, alkoxyalkylureido, thioureido,alkylthioureido, hydroxyalkylthioureido, alkoxyalkylthioureido,heterocyclylureido or heterocyclylcarbonylamino group, and R is ashereinbefore defined), which compounds are described in and includedwithin the claims of the specification of our copending application Ser.No. 729,394 filed May th 1968, and

(wherein R and R are as hereinbefore defined) with an amine of generalformula R NH (wherein R is as hereinbefore defined) in an inert organicsolvent such as dimethylformamide or a lower alkanol (e.g. methanol orethanol) at a temperature between 0C. and 100C.

The epoxides of general formula II may be prepared by known methods forthe preparation of epoxides, eg by the reaction of epichlorohydrin witha phenol of the general formula:

III

(wherein R and R are as hereinbefore defined, and M represents ahydrogen or alkali metal atom) in an aqueous or inert organic solvent,such as dimethylformamide or a lower alkanol (e.g. ethanol), at atemperature between 0C. and 100C. When N represents a hydrogen atom, thereaction is carried out in the presence of a basic condensing agent(e.g. potassium carbonate, sodium hydroxide or sodium ethoxide).

Compounds of general formula 111 wherein M represents an alkali metalatom may be prepared by known methods for the preparation of alkalimetal derivatives of phenols, for example by treating a compound ofgeneral formula 111 wherein M represents a hydrogen atom with a solutionof an alkali metal alkoxide (e.g. sodium ethoxide) in a lower alkanol(erg. ethanol).

Compounds of general formula Ill wherein M represents a hydrogen atommay be prepared by known methods such as heating an ester of the generalformula:

OOCR

(wherein R and R are as hereinbefore defined) with a catalyst, forexample aluminium chloride, at a temperature between 130C. and 180C.,optionally in the presence of an inert organic solvent such as 1,l,2,2-tetrachloroethane.

Compounds of general formula IV may be prepared by known methods for thepreparation of esters of palkanamidophenols.

The compounds of general formula 1 may be 'converted into acid additionsalts by known methods, eg by the action of an acid on the compounds ofgeneral formula I in an appropriate solvent such as diethyl ether. Theacid addition salt which isformedis precipi-' tated, if necessary afterconcentration of its solution, and is separated by filtration ordeca'ntation.

For use in medicine, the compounds of general formula l are employed assuch or in the form of non-toxic acid addition salts (i.e. saltscontaining anions which are non-toxic atthe dosages used) such as saltsderived from inorganic acids (e.g. hydrochlorides, hydrobromides,phosphates, sulphates and nitrates) and from organic acids (e.g.oxalates, lactates, tartrates, acetates, salicylates, citrates,propionates, succinates, fumarates, maleates,methylene-bis-B-hydroxynaphthoates, gentisates andD-di-p-toluoyl-tartrates.

By the term known methods as used in this specification is meant methodsheretofore used or described in the literature.

The following Examples illustrate the preparation of compounds of thepresent invention.

EXAMPLE 1 A mixture of 5-acetamido-2-(2,3-epoxypropoxy)acetophenone (17g.), isopropylamine ml.), and dry ethanol (100 ml.) was heated underreflux for 24 hours. The excess of isopropylamine and ethanol wasevaporated and the residue was dissolved in chloroform. The solution wasextracted with dilute hydrochloric acid and the acid extract was madealkaline with sodium hydroxide and then extracted with chloroform. Thechloroform solution was dried and evaporated. The residue was treatedwith light petroleum and the solid obtained was recrystallised fromethyl acetate to give 5'-acetamido-2'-(2-hydroxy-3-isopropylaminopropoxy)acetophenone, m.p. 13l-134C.

The 5-acetamido-2-(2,3-epoxypropoxy)acetophenone used as startingmaterial was prepared as follows:

5'-Acetamido-2'-hydroxyacetophenone prepared according to M. Julia & M.Baillarge, Bull. Soc chim. Fr., 1952, 639) was dissolved in the minimumamount of dry ethanol. A solution of sodium ethoxide, prepared fromsodium (2.3 g.) and ethanol, was added and the solid which separated wasremoved by filtration, washed with a little dry diethyl ether and driedin a vacuumdesiccator overnight..The solid was placed in a Soxhletextractor and a boiling solution of epichlorohydrin (28.3 g.) in ethanolwas used to extract the solid overnight. Diethyl ether was added to thecooled solution, the sodium chloride was filtered off and the filtratewas evaporated. The residue was extracted with benzene and the extractevaporated to give 5'-acetamido-2'-(2,3-epoxypropoxy)acetophenone, m.p.-l12C.

- EXAMPLE 2 2-(2,3-Epoxypropoxy)-5- propionamidoacetophenone (7 g.),isopropylamine (40 g.) and methanol (200 ml.) were heated together underreflux for 1 9% hours. The reaction mixture was concentrated underreduced pressure and the residual oil was treated with N hydrochloricacid and ethyl acetate. The acid extract was brought to pH 11 with 2Naqueous sodium hydroxide solution and then extracted with chloroform.The dried chloroform extract was concentrated to give an oil, which wastreated with diethyl ether to give2'-(2-hydroxy-3-isopropylaminopropoxy) -5'-propionamidoacetophenone (5.5g.), m.p. 110-1l3C.

The following compounds were prepared similarly:2'-(2-hydroxy-3-isopropylaminopropoxy)-5'- isobutyramidoacetophenone,m.p. lO2-104C., from 2-(2,3-epoxypropoxy)-5- isobutyramidoacetophenone;2-(2-hydroxy-3-isopropylaminopropoxy5'- valeramidoace'tophenone, m.p.129131C., from 2-(2,3-epoxypropoxy)-5fvaleramidoacetophenone;2'-(2-hydroxy-3-isopropylaminopropoxy)-5- isovaleramidoacetophenone,m.p. 1l011lC., from 2'-(2,3-epoxypropoxy)-5- isovaleramidoacetophenone;1 5'-hexanamido-2-(2-hydroxy-3-isopropylaminopropoxy)acetophenone, m.p.l41l42C., from 2-(2,3-epoxypropoxy)-5- I hexanamidoacetophenone;2-(2-hydroxy-3-isopropylaminopropoxy)-5'- octanamidoacetophenone, m.p.1'171 19C., from 2-(2,3-epoxypropoxy')-5- octanamidoacetophenone;2-(2-hydr0xy-3-isopropylaminopropoxy)-5T- nonanamidoacetophenone, m.p.108109C., from crude 2'-(2,3-epoxypropoxy)-5- nonanamidoacetophenone;5-butyramido-2'-(2-hydroxy-3- methylaminopropoxy)acetophenone, m.p.143-146C., from 5-butyramido-2-(2,3-epoxypropoxy)acetophenone (preparedas described in Example 4), and2-(3-tert-butylamino-2-hydroxypropoxy)-5'- butyramidoacetophenone, mp.138C., from 5- butyramido-2'-(2,3-epoxypropoxy)acetophenone (prepared asdescribed in Example 4). 2'-(2,3-Epoxypropoxy)-5'-propionamidoacetophenone used as starting material was prepared asfollows:

p-Propionamidophenol (82 g.; prepared according to Fierz-David andKuster, Helv. chim. Acta, 1939, 22 82) acetyl chloride (40 g.) andbenzene (1 litre) were heated under reflux until a solution formed (1hour). This solution was cooled and added to water and the precipitatedsolid was removed by filtration, washed with water and dried to givep-propionamidophenyl acetate (50 g.), m.p. 100105C. A mixture ofppropionamidophenyl acetate (50 g.) and aluminum chloride (100 g.) washeated at 170C. for 5 hours. An excess of water was added to the cooledmixture and the solid residue was removed by filtration andrecrystallised from aqueous ethanol to give 2-hydroxy-5'-propionamidoacetophenone (16 g.), m.p. 116-120C. A solution of2'-hydroxy-5'- propionamidoacetophenone (11.5 g.) in ethanol (.200 ml.)was added to an ethanolic solution of sodium ethoxide prepared fromsodium (1.27 g.) and ethanol (200 ml.). The resulting solution wasevaporated to dryness under reduced pressure. Benzene was added and thesolution was again evaporated to dryness under reduced pressure.Dimethylformamide (100 ml.) and m.p. 137139C., from 2-hydroxy-5'-valeramidoacetophenone;

2(2,3-epoxypropoxy )-5 isovaleramidoacetophenone, m.p. -l00C.,

from 2'-hydroxy-5-isovaleramidoacetophenone; 2-(2,3epoxypropoxy)-5'-hexanamidoacetophenone, mp. 136-137C., from 5-hexanamido-2hydroxyacetophenone; 2-(2,3-epoxypropoxy)-5'- octanamidoacetophenone,m.p. 1 33134C., from 2'-hydroxy-5-octanamidoacetophenone, crude2-(2,3-epoxypropoxy)-5 nonanamidoacetophenone from hydroxy-S-nonanamidoacetophenone. The intermediate i 2-hydroxy-5-isobutyramidoacetophenone was prepared as follows:

Isobutyric anhydride (17.5 g.) was added dropwise with stirring to amixture of 5' 2- hydroxyacetophenone (13.7 g.; prepared according to M.Julia & M. Baillarge, Bull, Soc. chim. Fr., 1952, 639), isobutyric acid(10 g.), and water (25 ml.) which was heated on the steam-bath. Heatingand stirring were continued for a further 1 hour, and the mixture wascooled. After the addition of a further quantity (2.5 ml.) of water, asolid. separated. This was filtered off, dried, and triturated withdiethyl ether. The solid was filtered off and dried to give2-hydroxy-5'- isobutyramidoacetophenone (14.15 g. m.p. l31-132C.

The following compounds were prepared similarly:

2'-hydroxy-5'-va1eramidoacetophenone, m.p.

1.12115C.; 1 2'-hydroxy-5-isovaleramidoacetophenone, m.p.

ll9l20C.; 5-hexanamido-2'-hydr0xyacetophenone, m.p.

121C.; 2-hydroxy-5-octanamidoacetophenone, m.p.

108110C., and 2'-hydroxy-5'-nonanamidoacetophenone, m.p.

' EXAMPLE 3 2'-(2,3-Epoxypropoxy)-5-propionamidopropiophenone (14 g.),isopropylamine (80 g.) and methanol (200 ml.) were heated together underreflux for l /2 hours. The reaction mixture was then concentrated underreduced pressure to give a residual oil which was recrystallisedfrom-ethyl acetate to give 2'-(2-hydroxy-3-isopropylaminopropoxy)-5-propionamidopropiophenone (13 g.), m.p.89-92C.

2'-(2,3-Epoxypropoxy)-5'-propionamidopropiophenone used as startingmaterial was prepared as follows:

A solution of 2'-hydroxy-5-propionamidopropiophenone (30 g.-; preparedaccording to Raval and Thakor, J. Indian Chem. Soc. 1961 38, 421) inethanol and (200 ml.) was added to an ethanolic solution of sodiumethanoxide prepared from sodium (3.12 g.) and ethanol (200 ml.). Theresulting solution was evaporated to dryness under reduced pressure.Benzene was added and the solution was again evaporated to dryness underreduced pressure. Dimethylformamide (200 ml.) and epichlorohydrin (50ml.) were added and the solution was heated at 100C. for 4 hours. Thesolution was concentrated under reduced pressure to give an oil whichwas then treated with water to give a solid which was recrystallisedfrom ethyl acetate to give 2-(2,3-epoxypropoxy)--propionamidopropiophenone 18.4 g.) m.p. 1l4l18C.

EXAMPLE 4 Crude 5-butyramido-2'-(2,3-epoxypropoxy)acetophenone (16 g),isopropylamine (20 g.) and ethanol (100 ml.) were heated together underreflux for 4 hours. The reaction mixture was concentrated under reducedpressure and theresidual oil was dissolved in N hydrochloric acid. Theacid solution was extracted with ethyl acetate, theethyl acetate layersbeing discarded. The acidic solution was brought to pH 11 with 2Naqueous sodium hydroxide solution and then extracted with chloroform.The dried chloroform extracts were concentrated under reduced pressureto give an oil which was crystallised from a mixture of ethanol anddiethyl ether to give 5'-butyramido-2-(2-hydroxy-3-isopropylaminopropoxy)acetophenone (3 g.), m.p. 119l23C.

Similarly prepared was cyclohexylamino-2-hydroxypropoxy)acetophenone,m.p. 112113C.

Crude 5-butyramido-2-(2,3-epoxypropoxy)acetophenone used asstartingmaterial was prepared as follows:

p-Butyramidophenol (58 g.; prepared according to Fierz-David and Kuster,loc.cit.), acetyl chloride (25.4 g.) and benzene (500 ml.) were heatedtogether under reflux until a solution formed (12 hours). This solutionwas cooled and treated with water. The benzene layer was separated andthe aqueous layer was again extracted with benzene.

The combined benzene extracts were dried and evaporated to dryness underreduced pressure to give pbutyramidophenyl acetate (38 g.) as anoff-white solid, mp. 102-l03C. A mixture of p-butyramidophenyl acetate(38 g.), aluminium chloride (80 g.) and 1,l,2,2-tetrachloroethane (250ml.) was heated at 140C. for 3 hours. The reaction mixture was cooledand treated with iced water. The tetrachloroethane layer was separatedand the aqueous layer was extracted with chloroform. The combinedorganic layers were extracted with 2N aqueous sodium hydroxide and thealkaline solution was acidified to pH 5 with concentrated hydrochloricacid. The acidified solution was extracted with chloroform and thechloroform extract was dried and concentrated under reduced pressure togive 5'-butyramido-2-hydroxyacetophenone 15.6 g.), m.p. 114l17C. Asolution of 5-butyramido-2'- hydroxyacetophenone (15.6 g.) in ethanol(100 ml.) was added to an ethanolic solution of sodium ethoxide whichwas prepared from sodium (1.62 g.) and ethanol (100 ml.). The resultingsolution'was evaporated to dryness under reduced pressure anddimethylformamide (100 ml.) was added to the solid'residue. Ap-

proximately ml. of dimethylformamide was removed by distillation underreduced pressure. Epichlorohydrin ml.) was added and the solution washeated at 100C. for 4 hours. The solution was concentrated under reducedpressure to give a residual oil which was treated with water to'give asolid. The solid was dissolved in ethanol and the resulting solution wastreated with charcoal, filtered and concentrated under reduced pressureto give crude 5-butyramido- 2-(2,3-epoxypropoxy)acetophenone (16 g.),m.p. 1101 16C.

The crude compound may be purified by recrystallisation from ethylacetate, after, treatment with decolourizing charcoal, to give pure5'-butyramido-2'-(2,3- epoxypropoxy)acetophenone, m.p. 136138C.

EXAMPLE 5 5-Butyramido-2-(2-hydroxy-3-isopropylaminopropoxy)acetophenone(3.36 g.; prepared as described in Example (4) was dissolved inanhydrous methanol (50 ml.), and anhydrous diethyl ether (200 ml.)added. A saturated solution of anhydrous hydrogen chloride in anhydrousdiethyl ether (25 ml.) was added dropwise with stirring. An oil wasprecipitated, which crystallized on further stirring. The solid wasfiltered off and recrystallized from a mixture of anhydrous methanol andanhydrous diethyl ether to give 5-butyramido-2'-(2-hydroxy-3-isopropyl'amino-propoxy)acetophenone hydrochloride (2.5 g.),m.p. l4ll43C.

EXAMPLE 6 Boiling solutions of 5'-butyramido-2-(2hydroxy-3-isopropylaminopropoxy)acetophenone (3.36 g.; prepared as described inExample (4) in' acetone (250 ml.) and of D-tartaric acid 1.5 g.) inacetone (50 ml.) were mixed, and the mixture allowed to cool overnight.The solid which separated was filtered off to give5-butyramido-2'-(2-hydroxy- 3-isopropylaminopropoxy)acetophenoneD-tartrate (3.7 g.)., m.p. 179C.

The present invention includes within its scope pharmaceuticalcompositions which comprise at least one of the benzene derivatives ofgeneral formula I, or a non-toxic acid addition salt thereof, inassociation with a pharmaceutically-acceptable carrier or coating. Inclinical practice the compounds of the present invention will normallybe administered orally or parenterally.

'Solid compositions for oral administration include compressed tablets,pills, powders and granules. in such solid compositions, at least one ofthe active compounds is admixed with at least one inert diluent such asstarch, sucrose or lactose. As is normal practice the compositions mayalsocontain additional substances other than inert diluents, e.g.lubricating agents, such as magnesium stearate.

Liquid compositions for oral administration includepharmaceutically-acceptable emulsions, solutions, suspensions, syrupsand elixirs containing inert diluents commonly used in the art, such aswater and liquid par-, affin. Besides inert diluents such compositionsmay also contain adjuvants, such as wetting and suspending agents, andsweetening, flavouring, perfuming and preserving agents. According tothe invention, the compounds for oral administration also includecapsules of absorbable material, such as gelatin, containing one or moreof the active substances with or without the addi-- tion of diluents orexcipients.

through a bacteria-retaining filter, by incorporation of sterilisingagents in the compositions, by irradiation or by heating. They may alsobe manufactured in the form of sterile solid compositions which can bedissolved in sterile water or some other sterile injectable mediumimmediately before use.

The percentage of active ingredient in the composi tions of theinvention may be varied so that a suitable dosage is obtained.Obviously, several unit dosage forms may be administered at about thesame time. The dose employed depends upon the desired therapeuticeffect, the route of administration and the duration of the treatment.In the adult, the doses are generally between O.l and 0.5 mg./kg. bodyweight per day by intravenous administration. However, the new compoundswill usually be self-administered by the patient and oral administrationis therefore preferred, by which route of administration the doses aregenerally between 1 and 10 mg/kg. body weight per day in the adult.

The following Examples illustrate pharmaceutical compositions accordingto the invention.

EXAMPLE 7 Tablets of the formula:

2(2-hydroxy-3-isopropylaminopropoxy)-5'-pro- 20 mg.pionamidopropiophenone lactose 49.5 mg. starch 20 mg. dextrin 20 mg.magnesium stearate 0.5 mg.

were prepared by intimately mixing the amine, lactose, starch anddextrin and passing the mixture through a 60-mesh British Standardsieve. After addition of the magnesium stearate, the mixture wasgranulated to a suitable size and the granules compressed to formtablets.

EXAMPLE 8 An injectable solution of the following compositio i:

2-(2-hydroxy-3isopropylaminopropoxy)-5'- 2.5 g.propionamidopropiophenone hydrochloride distilled water up to 100 ml.

was prepared by dissolving the amine hydrochloride in the distilledwater. The solution was filtered and filled into ampoules which weresterilized in an autoclave.

EXAMPLE 9 Tablets of the formula:

5'-butyramido-2-(Z-hydroxy-S-isopropylaminopropox- 20 mg.

y)acetophcnone lactose 49.5 mg.

starch 20 mg.

-Continued dextrin 20 mg.

magnesium stearate ()5 mg.

were prepared by intimately mixing the amine, lactose, starch anddextrin and passing the mixture through a -mesh British Standard sieve.After addition of the magnesium stearate, the mixture was granulated toa suitable size and the granules compressed to form tablets.-

We claim:

1. A pharmaceutical composition which comprises, as the activeingredient, an effective amount for the treatment or prophylaxis ofangina pectoris 'or cardiac arrhythmia of a compound of the formula:

OCH CHCH NHR 3 OCH CIJHCH NHR (II=O R2 wherein R representsalkanoylamino of one through nine carbon atoms, R represents alkyl ofone through six carbon atoms, and R represents alkyl of one through sixcarbon atoms or cycloalkyl of three through six carbon atoms, or anon-toxic acid addition salt thereof, when administered orally in anamount between 1 and 10 mg/kg body weight per day and when administeredintraveneously in an amount between 0.l

, and 0.5 mg/kg body weight per day.

3. The method according to claim 2 in which the said compound is5'-butyramido-2-(2-hydroxy-3- isopropylaminopropoxy) acetophenone or anon-toxic acid addition salt thereof.

* l l= l= I

1. A PHARMACEUTICAL COMPOSITION WHICH COMPRISES, AS THE ACTIVEINGREDIENT, AN EFFECTIVE AMOUNT FOR THE TREATMENT OR PROPHYLAXIS OFANGINA PECTORIS OR CARDIAC ARRHYTHMIA OF A COMPOUND OF THE FORMULA:
 2. Amethod of treatment or prophylaxis of a cardiac disorder in a patientsuffering from angina pectoris or cardiac arrhythmia which comprisesadministering orally or intravenously to the patient a compound of theformula:
 3. The method according to claim 2 in which the said compoundis 5''-butyramido-2''-(2-hydroxy-3-isopropylaminopropoxy) acetophenoneor a non-toxic acid addition salt thereof.